About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

December 14, 2004

The Coming Oncology

Posted by Derek

I've had a number of comments on my post below about the changing cancer market, and they deserve some follow-up. One very good point that was made is that this change is really a race between several factors: the narrowing of individual markets as we find out the reasons for efficacy could be balanced out by the ease that this could bring to the design of clinical trials. After all, it should be easy to get good data if you have a clearer idea of which patients are most likely to respond. (Every major drug company is plowing money into biomarker research for just this reason.)

But if you design your trial on the basis of a specific biomarker, I assume that you'll get a specific approval based on that, too. You're trading larger market potential for a higher clinical and regulatory success rate - and believe me, I'm far from suggesting that that's a bad trade. But it'll be an interesting decision in some cases. In the short term, I would expect to see some companies forgoing the use of narrow biomarker-driven trials in an attempt to go for the bigger money. But as the everyone-prescribes-for-everything model for the oncology market breaks down, that'll become less and less of an option.

How many years is that breakdown going to take? It's hard to say. Some areas are going to be way ahead of the rest of the field - for example, it might be happening right in front of us with Iressa, but in other markets we don't have a clue. In general, I'd say that twenty years will see the transformation well underway, but I could be off in either direction. Along the way, there are going to be some nasty surprises for the companies involved as they find that their existing or in-development drugs have suddenly contracted to much smaller roles.

Another thing to think about is how many new drugs we're going to need, versus combinations of existing ones. You'd think that the latter option would cover a lot of ground, but I think that the emergence of resistant tumor lines will keep everyone searching for new compounds. Oncology could end up looking a bit like anti-infectives, although the big difference is the individual occurrence of resistant tumors, rather than the far more challenging spread of resistant organisms.

So you'll end up with courses of treatment that look like this: sequence the patient and a sample of their cancerous cells, which will suggest the first-line therapy. Then if that doesn't knock everything down, you move to the next ones on the list (which will look slightly different under each of those first options), and switch to that, keeping an eye out over the next few years for the need to switch to a third agent or combination, and so on.

How will drug companies deal with these changes? A colleague of mine suggested that the larger outfits will probably fare better, because they'll be able to hold a portfolio of cancer drugs that will add up to something. The risk of changing market sizes will be spread out across several agents. Smaller companies may have to explicitly target smaller markets, which you'd think would lead to fewer stock-market skyrockets like Imclone and OSI. These would also seem to be good candidates for in-licensing from the bigger companies looking to fill gaps in their holdings.

But if you design your trial on the basis of a specific biomarker, I assume that you'll get a specific approval based on that, too. You're trading larger market potential for a higher clinical and regulatory success rate...

Approval may be coupled to a specific biomarker, but presumably the idea is to count on off-label use and hope reimbursement issues can be overcome.

Thanks for acknowledging my post. But a further response to your guess that it will take 20 years to see the transformation to targeting smaller populations. I'd be very very surprised if the transformation weren't ancient history by then for one simple reason. Economics. If a drug company runs a big (expensive) trial that has 10-20% response rate other outfits will produce a diagnostic test to edit out the non-responders before wasted treatment or they will produce a targetted treatment that works on roughly the same population - but with vastly cheaper trial costs. The go-for-everyone-and-hope-to-get-20% responders will soon go broke.

BTW - You expect the big companies to be the survivors here, but the big companies have a long history of being a little suicidal in trying to expand indications. Often resulting in failed trials. If they continue this mindset ... .

Yep, I think that's what people will be trying for. What I'm wondering is when the hopes for off-label use will start to fade. . .not for a while, but fade they eventually will. But who knows, I may spend the rest of my career (25 years?) under the current rules.

I hope personalized medicine comes true with a vengence, especially for cancer drugs. It would be great if we could avoid giving toxic chemo drugs except to people who have a real chance to benefit from them.

I wonder, though, how hard will it be to identify key biomarkers. The industry is still not too great at predicting which drugs will really succeed. Will we have the same problem identifying useful biomarkers?

If a company runs very targeted trials, believing that one or a few biomarkers will be predictive, could that actually increase failure rates? Conversely, if a company tries to look at many biomarkers, could that increase trial costs?

You're right; there are bound to be a few pratfalls when trials get run through a mistaken biomarker hypothesis. It'll be important to not let the whole idea get a bad reputation if there are a couple of complete flops in the early going.

Correct me if I'm wrong, but aren't there already several new targeted therapies on the market besides Iressa, such as Herceptin (Her2), Imclone's Erbitux (EGFR), Avastin (VEGF) etc. And in the pipeline you have several gene therapy drugs, angiogenesis drugs, monoclonal antibodies. The trick is to find targets that can be found on serveral different kinds of cancers to have a broad market, which is why the approval of Avastin is so exciting in the cancer therapy field and why several other companies are interested in developing other angiogenesis inhibitors (which inhibit the growth of new blood vessels in tumors). I think targeted therapies are already a major focus and its only a matter of time before there are enough on the market so that individuals will have a treatment regimen that is specific to their own tumor. It will be here sooner than you think.

Sami, I hope you're right, but I trust you won't take offense if I quibble with some of your examples.

Herceptin and Erbitux are certainly targeted therapies, directed at Her2- and EGFR-expressing tumors, respectively. But for all the interest and attention they've garnered, their clinical benefits don't strike me as overwhelming. If these two are representative of what targeted therapies are likely to offer in the near term, I think it will be a big disappointment.

I'm unclear how Avastin qualifies as a targeted therapy. Knowing how it works, I could imagine targeting it to patients whose tumors overexpress VEGF. But unlike with Herceptin and Erbitux, the prescribing info doesn't mention targeting patients in that way. I didn't follow Avastin's development in great detail, though. Is there data to suggest it works better against VEGF-overexpressing tumors? If so, any insight on why that isn't part of the approved indication?

I would love to see gene therapies succeed in the near term. However, I think only a minority, at best, would qualify as targeted therapies. (Unless we're working from different definitions?) And, having devoted a significant chunk of my career trying (unsuccessfully) to develop gene therapies, I've become sadly skeptical that many of them will reach the market in the next 5-10 years. I'd love to be wrong, but....

I agree with most of what you said, but I think I am just more optimistic. I think Heceptin and Erbitux are only the beginning and soon there will be more better targeting drugs to come.

As for Avastin, most tumors do overexpress VEGF, and I think this is why they are not specifically addressing a subset of patients. (I am guessing that angiogenesis inhibitors that target other angiogesis factors not as prevelant as VEGF will be more selective for patient responders). Maybe because of this Avastin isn't really a targeting drug, but I think of it as one because it was specifically developed to target VEGF. Actually, according a review on Avastin it suggests that resistance to VEGF targeting drugs does occur when the tumor starts to us PDGFR-beta dependant pericyte recruitment as opposed to endothelial cells dependent on VEGF (Nature Reviews Drug Discovery 3:391)

As far as gene therapy goes, your right, but I think there will be more and more targeting vectors/liposomes. The reason for this is to target tumor as oppossed to normal cells, but isn't this still a form of targeting. If you are targeting any kind of tumor marker its likely not going to be on 100% of the tumors and therefore not target all patients.

If the percent of responders is high enough, I agree there will be no screening before treatment at least right now. But someday, I think when screening does become common, you may not give things like Avastin to people who do not overexpress VEGF, even though today we do.

I also think most of the drugs in the pipeline are developed to targeted something these days, whether they end up being as specific as they were thought to be is another story. The way I see it is that targeting drugs are here already, but the screening won't necessarily come until there are many more approved targeting drugs to chose from.

Maybe I am just overly optomistic (perhaps because I haven't been in the business too long, or maybe because my PI in my last lab was sometimes unbearably optimistic).

Here's some timely support for your argument about targeting tests for already known drugs (although it's outside oncology). A testable genetic variation that may predict which patients will benefit from antidepressants.

Note that this links to a post on DB's Medical Rants, which contains links to the news story. Seemed only fair to link Med Rants rather than directly to the story, since that's where I saw it first. Sorry that the link is cut-and-paste. My HTML skills are still weak.

Good discussion. Wrt/ personalized medicine, I think we're still going to need A Whole Lot Of New Drugs in addition to new combinations of existing drugs (NCOED). People need to start thinking NOW about NEW ways to economically incentivize drug discovery in the age of personalized medicine.